SUMMARY The majority prostate cancers are indolent and do not affect patient's survivals, yet the patients are subjected to overtreatment suffering from treatment side effects, affecting patient's quality of life. Current cancer characters such as grade, stage, serum PSA and nomogram only predict clinical behavior to a certain degree, and do not sufficiently distinguish patients with aggressive (e.g. metastatic) or less aggressive tumors. Developing biomarkers to accurately stratify these patients become urgent task. Thus we propose to use systematic approaches to define protein and pathway network signatures that can distinguish indolent and a form of aggressive, metastatic, prostate cancer applying our Novel Proteomic Pathway array integrated with genomics via bioinformatics. Specifically, we will use a novel proteomic pathway array to identify proteins in key cellular signaling pathways that are differentially expressed or phosphorylated in non-metastatic vs. cancer with metastatic potential. Next, we will determine the association of signal pathway proteins with the clinical outcome of metastasis using high throughput tissue micro arrays. The functional relevance of the proteins identified will be tested in vitro and in vivo. Overall this study uses a unique proteomics and systems biology approach to identifying new biomarkers, and possible therapeutic targets, for metastatic prostate cancer through the elucidation of distinct regulatory network that underlies the biology of the prostate cancer. The advantage of combined expertise of our highly productive and collaborative researchers integrating various high through proteomic and genomic platform with innovative bioinformatics approaches will ensure the successful execution of this proposal. The biomarkers identified from this proposal will greatly improve current strategies to stratify prostate cancer patients between non-metastatic and metastatic disease.